APA 2014: New Research – Part 1


Highlights of the American Psychiatric Association (APA) 167th annual meeting, New York NY, May 3-7, 2014 –  The following articles summarize some noteworthy studies presented at this year’s APA annual meeting.  More topics will be covered in Part 2 which will be published July 9.

Major depressive disorder (MDD)
Anxiety disorders

Major depressive disorder (MDD) Four studies reported efficacy results for vortioxetine (Lu-AA21004), a novel antidepressant that acts on multiple serotonin receptors (5-HT3 and 5-HT7 antagonist, 5-HT1A agonist, 5-HT1B partial agonist) and on serotonin reuptake by 5-HT transporter inhibition (Adell A. IDrugs 2010;13:900-910). The drug was approved by the Food and Drug Administration (Brintellix) in 2013 for the treatment of MDD.

The first study randomized 608 MDD patients to one of two fixed doses of vortioxetine (15 or 20 mg/day), active control (duloxetine 60 mg/day) or placebo for 8 weeks (Boulenger et al. APA 2014; P3-54; now published as Boulenger et al. Int Clin Psychopharmacol 2014;29:138-149; free full text at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3979887/pdf/yic-29-138.pdf). Both study doses were superior to placebo in mean change from baseline in MADRS total score at 8 weeks; the mean treatment difference was -5.5 points with the 15-mg dose and     -7.1 points with the 20-mg dose. The treatment discontinuation rate was 22.5% and 17.2% with vortioxetine 15 mg and 20 mg versus 15.8% with placebo. The most common adverse effects were nausea, headache, diarrhea, dry mouth, dizziness and excessive sweating.

A second 8-week study comparing vortioxetine 15 mg or 20 mg/day with duloxetine 60 mg/day or placebo in 614 MDD patients reported similar results (Mahableshwarkar et al. APA 2014; NR9-01). The least-squares mean change from baseline in MADRS total score was -14.30 and -15.57 with the 15-mg and 20-mg doses versus -12.83 with placebo; differences were statistically significant for the vortioxetine 20-mg dose. The 20-mg dose was also shown to be effective in a third study in 462 MDD patients (Jacobsen et al. APA 2014; NR9-06). The mean change in MADRS total score at 8 weeks was -14.41 with vortioxetine 20 mg versus -10.77 with placebo. Differences were not significant for the 10-mg dose (-12.96; p=0.058). A fourth trial using lower doses of vortioxetine (10 mg and 15 mg/day) showed no significant effect on MADRS scores (Mahableshwarkar et al. APA 2014; NR9-02). In the U.S. product monograph, the recommended starting dose of vortioxetine is 10 mg once-daily, increased to 20 mg/day as tolerated.

Two reports evaluated the efficacy of desvenlafaxine, approved by the FDA (Pristiq) in 2013 for the treatment of MDD. The first analysed relapse prevention in two studies (McIntyre et al. APA 2014; NR9-09). Study 1 was a 6-month placebo-controlled study of desvenlafaxine 50 mg/day. Overall relapse rates were significantly lower with desvenlafaxine versus placebo (14% vs. 28%); a treatment effect was seen at month 2. In study 2, subjects were randomized to desvenlafaxine 200 mg or 400 mg/day or placebo. Overall relapse rates at 6 months were 24% versus 42% with placebo; an earlier onset of action (month 1) occurred with higher dosing.

A pooled analysis of 8 double-blind studies (n=3384) examined whether efficacy with desvenlafaxine was affected by body-mass index (BMI) (McIntyre et al. APA 2014; N9-10). There were significant improvements in HAMD-17 scores at week 8 with desvenlafaxine 50 or 100 mg/day across the range of BMI. There was no clear correlation between dosing, BMI and clinical response, indicating that BMI does not significantly affect response to desvenlafaxine.

Vilazodone, the SSRI/5-HT1A partial agonist, was approved by the FDA (Viibryd) based on the results of two placebo-controlled studies (combined n=863). A post-hoc pooled analysis examined the rates of early sustained response (response at week 1 or 2 and at endpoint) and sustained response (last two visits) to treatment (Jain et al. APA 2014; NR9-37). Vilazodone was superior to placebo both in the proportion achieving an early sustained response (9% vs. 4%) and a sustained response (32% vs. 22%).

Ketamine was evaluated in a study of 72 patients with treatment-resistant depression (Murrough et al. APA 2014; NR5-05). Subjects were randomized to receive a single infusion of ketamine 0.5 mg/kg or midazolam 0.045 mg/kg. The primary endpoint was change from baseline in MADRS score 24 hours post-infusion. Both treatments showed a significant decrease in MADRS score (ketamine -16.5 points; midazolam -8.8); the response rate was 63.8% vs. 28.0%, respectively. Response rates at Day 7 were 45.7% and 18.2%, respectively. Also noteworthy was a separate study of ketamine in obsessive-compulsive disorder (OCD) (Rodriguez et al. APA 2014; NR4-01). The study randomized 10 patients to ketamine 0.5 mg/kg or sham infusion with crossover at 1 week. The responder rate was 50% at day 7; the rate was 40% at Day 14 for the subset initially randomized to active drug.

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Anxiety disorders
A slow taper over 8 weeks appears to be effective in minimizing withdrawal symptoms in patients with panic disorder treated with clonazepam or paroxetine (Nardi et al. APA 201; NR9-33). The study involved 94 patients on treatment for at least three years and who were candidates for treatment discontinuation (asymptomatic for at least a year). The mean doses at baseline were clonazepam 1.9 mg/day, and paroxetine 38.9 mg/day.

The daily dose of clonazepam was reduced every two weeks by 0.5 mg/week until a dose of 1 mg/day was reached; the daily dose was then reduced by 0.25 mg/week. The daily dose of paroxetine was reduced by 10 mg every two weeks until a dose of 20 mg/day was reached, whereupon the daily dose was reduced by 5 mg/week. A total of 26% of patients required a longer tapering period, and 12% required adjunctive carbamazepine or mirtazapine. Withdrawal symptoms occurred in 75.3% but were generally mild. Clonazepam-treated patients were more likely to achieve drug-free status and had fewer withdrawal symptoms compared to paroxetine-treatment patients.

A review of small randomized trials has concluded that there is evidence to support the use of the alpha-blocker prazosin to treat nightmares and improve sleep in patients with post-traumatic stress disorder (Yoho S. APA 2014; P1-71). A total of 159 articles were identified. Overall, prazosin resulted in improvements in nightmares, sleep disturbance, and global PTSD severity and functional status compared to placebo. The presumed mechanism of action is a reduction in corticotropin-releasing hormone with prazosin.

We will continue our coverage of the APA in the next issue of NeuroSens.   

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